This invention relates to a process for modifying the effects of therapeutic administration of L-dopa, and to pharmaceutical preparations suitable for this purpose.
L-Dopa (L-3,4-dihydroxyphenylalanine) is used for the treatment of parkinsonism and Parkinson's disease. The cause of parkinsonism is thought to be a deficiency of the neurotransmitter dopamine, 2-(3,4-dihydroxyphenyl)-ethylamine, in the basal ganglia. Dopamine itself does not pass through the blood-brain barrier; for this reason, this compound is unsuitable for parkinsonism therapy. Consequently, treatment of parkinsonism is carried out by substitute therapy using high doses of L-dopa, a precursor of dopamine, which passes the blood-brain barrier. However, L-dopa is also a precursor of noradrenaline, so that its administration to a patient results in increased formation of noradrenaline. As a result, the metabolic equilibrium of the neurotransmitters noradrenaline and serotonin is disturbed in the brain.
Administration of L-dopa also leads to reduction in the activity of serotoninergic neurons. The result is agitation, motoric unrest, increased sexuality, insomnia, hypomanic reactions, and sometimes even hallucinations and delirious conditions, i.e., "L-dopa psychosis". These psychic disturbances normally cannot be overcome by conventional psychopharmacological agents, which simultaneously counteract the effect of the dopamine so that symptoms of the original parkinsonism returns.
It has been found that the psychopharmacological agent mepiprazole, 3-[2-(N'-m-chlorophenylpiperazino)-ethyl]-5-methylpyrazole, unlike other psychopharmaceuticals, has specific dopamine- and serotonin-potentiating activity and simultaneously has noradrenaline-blocking activity in the central nervous system. Thus, for example, dopamine reuptake according to Carlsson et al., Europ.J.Pharmacol. 5: 367 [1969], was inhibited by 50-70% in rats by administration of 20 mg./kg. of mepiprazole.
The turnover rate of transmitters in rats by the method of Anden et al., Metabolism of Amines in the Brain, Ed., G. Hooper, Macmillan 1969, p. 44, showed a reduction in serotonin turnover of about 50% and an increase in noradrenaline turnover by 60% following administration of 2.5 mg./kg. of mepiprazole. This combination of effects has not been observed heretofore in psychopharmaceuticals. These newly-found properties of mepiprazole permit normalization of noradrenaline and serotonin transmitter metabolism disturbed by the administration of L-dopa, that is, psychic side effects of L-dopa therapy are positively affected and the primary effect of dopamine is enhanced.
The preparation and certain pharmacological properties and medicinal uses of mepiprazole are disclosed in U.S. Pat. No. 3,491,097, incorporated herein by reference. Mepiprazole has for example, narcosis-potentiating effects typical of conventional psychopharmaceuticals. The properties of mepiprazole which are utilized in this invention could not be predicted from the properties set forth in the above reference. Based on the properties indicated in that reference, mepiprazole should have no advantages over other neuroleptics, in L-dopa therapy.